rs56248469

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000875.5(IGF1R):c.1784G>A(p.Arg595His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,140 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 6 hom. )

Consequence

IGF1R
NM_000875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 2.12

Publications

20 publications found

Variant links:

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

IGF1R Gene-Disease associations (from GenCC):

growth delay due to insulin-like growth factor I resistance
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

IGF1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018484533).

BP6

Variant 15-98913238-G-A is Benign according to our data. Variant chr15-98913238-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284570.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00067 (102/152288) while in subpopulation NFE AF = 0.00125 (85/68026). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGF1R	NM_000875.5	MANE Select	c.1784G>A	p.Arg595His	missense	Exon 8 of 21	NP_000866.1	P08069
	IGF1R	NM_001291858.2		c.1784G>A	p.Arg595His	missense	Exon 8 of 21	NP_001278787.1	C9J5X1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGF1R	ENST00000650285.1	MANE Select	c.1784G>A	p.Arg595His	missense	Exon 8 of 21	ENSP00000497069.1	P08069
IGF1R	ENST00000559925.5	TSL:1	n.1784G>A		non_coding_transcript_exon	Exon 8 of 10
IGF1R	ENST00000649865.1		c.1784G>A	p.Arg595His	missense	Exon 8 of 21	ENSP00000496919.1	C9J5X1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000644

AC:

162

AN:

251468

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00154

AC:

2253

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1086

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00196

AC:

2184

AN:

1111980

Other (OTH)

AF:

0.000795

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152288

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000748

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Growth delay due to insulin-like growth factor I resistance (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.37

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.010

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.0

PhyloP100

2.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.1

REVEL

Benign

0.13

Sift

Benign

0.54

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.18

MVP

0.63

MPC

0.77

ClinPred

0.022

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.34

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over